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Reducing neonatal infectious morbidity and mortality: joining up our thinking

Scientific meeting

Location

Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ

Overview

Theo Murphy scientific meeting organised by Dr Kirsty Le Doare, Dr Elizabeth Whittaker, Professor Beate Kampmann and Dr Chrissie Jones.

B cell with bacteria.

Whilst under-5 mortality has declined globally, neonatal mortality remains static, largely due to infection. Understanding how neonatal immune responses differ to adults will aid development of targeted neonatal infection prevention and management strategies. This meeting will discuss recent scientific advances and propose a research agenda for collaborative international research to reduce the burden of community and hospital-acquired neonatal infection.

The schedule of talks, speaker biographies and abstracts are available below. Recorded audio of the presentations are also available below.

Attending this event

This is a residential conference, which allows for increased discussion and networking. 

  • Free to attend
  • Advanced registration essential
  • Catering and accommodation available to purchase during registration 

Enquiries: Contact the Scientific Programmes team

Event organisers

Select an organiser for more information

Schedule of talks

13 February

Session 1 09:00-12:50

Neonatal infection, the burden and current management

5 talks Show detail Hide detail

Chairs

Dr Chrissie Jones, St George's, University of London, UK

09:05-09:25 5.7 million neonatal deaths and stillbirths: infections, organisms and measurement black holes

Professor Joy Lawn FMedSci, London School of Hygiene & Tropical Medicine, UK

Abstract

Of the annual 2.7 million neonatal deaths, the most recent estimates for 196 countries suggest that neonatal infections causes approximately 600,000 deaths, almost double the number of child deaths from malaria plus HIV/AIDS. Yet for neonatal infections (apart from tetanus) there is much slower mortality reduction, and very limited global health investment. If the closely linked burden of 2.6 million stillbirths could be accurately assessed for infection, and the impairment outcomes for survivors of neonatal infection were included then the associated burden would be even more striking. 

There are measurement black holes which impede evidence based investment and faster reduction of this burden, but could be targeted. For example, new analysis shows the important contribution of group B streptococcus to stillbirths, as well as neonatal invasive disease, with implications for cost-effectiveness of maternal vaccination. Some of the most important measurement black holes regarding neonatal infections will be detailed, highlighting opportunities for change, notably the following: aetiological data, stillbirth investigations including infection aetiology, impairment outcomes for survivors of neonatal infections, and measuring the coverage and quality of care.


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09:40-10:00 Gram-negative bacterial infections in the neonate – global epidemiology

Dr Julia Bielicki, St George's, University of London, UK

Abstract

Gram-negative bacterial infections, in particular sepsis caused by Gram-negative bacteria, can have devastating consequences during the neonatal period. Rising levels of antimicrobial resistance among Gram-negative bacteria globally are an additional cause for concern, as therapeutic options are limited. In particular, data from lower and middle income countries, where neonates experience a high burden of infections with considerable associated mortality and morbidity, demonstrate that many Gram negative isolates are resistant to both first- and second-line empiric regimens recommended by the World Health Organization. Furthermore, there are a number of reports of outbreaks caused by multidrug resistant Gram-negative bacteria in the setting of neonatal inpatient care. It has been estimated that up to 30% of neonatal deaths due to sepsis are attributable to multi-drug resistant bacteria, with extended-spectrum beta-lactamase producing Gram negative bacteria being among the main culprits. However, available surveillance data is of insufficient quality to gain robust insights into the global epidemiology of neonatal Gram-negative bacterial infections. Improved and integrated surveillance is necessary to identify the areas of greatest therapeutic need in this population. Currently available antibiotic treatment options are limited, and the potential effectiveness of other interventions has not been sufficiently studied. Alternative interventions range from non-invasive attempts to influence the colonising microflora (for example through increased mother-baby skin-to-skin contact) to the prophylactic use of monoclonal antibodies against key bacteria.

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10:50-11:10 Group B Streptococcal disease and neonatal susceptibility to infection

Professor Philipp Henneke, Center for Pediatrics and Center for Chronic Immunodeficiency, University of Freiburg, Germany

Abstract

Neonatal group B streptococcal sepsis is a highly inflammatory disease, where bacterial effectors induce cytokines leading to end organ failure, long term sequels and lethality. We have identified the interaction of streptococcal RNA and lipopeptides with Toll-like receptors and cytosolic sensors as key molecular events in this process. Moreover, tissue specific changes in immune cell composition under influence of the emerging microbiota substantially contribute to susceptibility to infection and course of the disease. Accordingly, manipulation of the site specific innate immune cell response on the cognate receptor level is a rational strategy for improving outcome in group B streptococcal sepsis.

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11:30-11:50 Global burden of congenital CMV infection

Professor Suresh Boppana, University of Alabama School of Medicine, USA

Abstract

Cytomegalovirus (CMV) is a leading cause of congenital infection worldwide. In the developed world, it is a leading non-genetic cause of childhood hearing loss and neurodevelopmental disabilities. The prevalence of congenital CMV infection is directly related to CMV seroprevalence in women of child-bearing age. Therefore, the populations in the developing world experience the higher prevalence of congenital CMV infection (1-5% of births) and are most likely driven by non-primary maternal infections. Although reliable estimates of prevalence and outcome from different regions of the world are not available, recent data demonstrating similar rates of hearing loss following primary and non-primary maternal infection have underscored the importance of congenital CMV infection in resource-poor settings.  Therefore, successful implementation of strategies to prevent or reduce the burden of congenital CMV infection will require heightened global awareness among clinicians and the general population and a better understanding of the factors associated with intrauterine transmission of CMV following non-primary maternal infections. This talk will highlight the global epidemiology of congenital CMV with particular emphasis on the disease burden in resource-poor settings.

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12:10-12:35 Neonatal innate immunity to RSV: from pathogenesis to protection

Dr Mirjam Belderbos, University Medical Center Groningen, The Netherlands

Abstract

Respiratory syncytial virus (RSV) is the leading cause of infant lower respiratory tract infection, accounting for 33.8 million episodes of acute respiratory tract infection and 66,000 – 199,000 deaths annually. Over 80% of severe RSV infections occur in otherwise healthy neonates and infants <6 months, urging for novel strategies to protect this vulnerable age group.

Toll-like receptor (TLR) responses play an essential role in the defence against RSV. Efficient viral clearance requires pathogen recognition through TLR4 and induction of a Th1-type immune response. In contrast, severe RSV disease is characterised by a Th2-type immune response, characterised by low levels of pro-inflammatory cytokines and high levels of IL-10. The distinct function of the neonatal TLR system, which is intrinsically biased against production of pro-inflammatory responses and favours production of IL-10, may predispose to severe RSV infection. This is supported by recent studies, which show that age-dependent differences in dendritic cells shape the immune response to RSV, and that neonatal dendritic cells require more co-stimulation than adult dendritic cells to induce protective responses.

The early postnatal period is essential for the development of the neonatal TLR system, and may provide a unique window of opportunity to prevent subsequent RSV bronchiolitis. For instance, environmental factors, such as breast feeding, presence of siblings and mode of delivery, have been shown to modulate postnatal TLR maturation. In addition, mechanistic studies have identified neonatal blood plasma as an important source of immune modulatory factors, which may provide novel targets to modulate neonatal innate responses and to optimise antiviral immunity.   

This talk will discuss how insights into the neonatal innate immune system can be exploited to reduce the global burden of RSV infection.  

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12:50-13:30

Lunch

Session 2 13:30-17:00

Why are neonates so susceptible?

2 talks Show detail Hide detail

Chairs

Dr Elizabeth Whittaker, Imperial College London, UK

13:30-14:00 The impact of maternal infections in pregnancy on the neonatal immune system

Dr Arnaud Marchant, Institute for Medical Immunology, Université Libre de Bruxelles, Belgium

Abstract

Epidemiological studies suggest that chronic infections during pregnancy impact the susceptibility of young children to homologous or heterologous pathogens. This impact probably involves multiple factors but maternal programming of the neonatal immune system is likely to be involved. The implementation of anti-retroviral therapy during pregnancy has markedly increased the number of HIV-exposed but uninfected (HEU) infants. Studies from low- and high-income countries indicated that HEU infants are at high risk of severe infections caused by a variety of pathogens. Immune abnormalities, including the decreased transfer of maternal antibodies and activation of the newborn immune system, as well as haematological toxicity of anti-retrovial therapy (ARVT) have been proposed as possible mechanisms. In a prospective birth cohort study conducted in Belgium, HEU infants had a two-fold higher risk of hospitalisation for infection as compared to HIV-unexposed infants. The results of this study will be presented and the identification of immunological biomarkers associated with severe infections will be discussed.

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14:15-14:45 Susceptibility to infectious disease in the newborn

Professor Tobias Kollmann, University of British Columbia, Canada

Abstract

Neonatal infection causes nearly 1 million deaths per year. This horrific clinical reality is often ascribed to a lower capacity of the newborn immune system to fend off invading microbes. However, there also is substantial evidence for an exuberant host immune response to infection in the newborn. This apparent contradiction (lower vs. higher immune activity) indicates that the often-used explanation (‘the newborn immune systems is less capable, i.e. immature’) does not capture this complex reality. The paradigm implicating age-specific regulatory adaptations rather than simply lower effector mechanisms for an increase in morbidity and mortality in early life fits the existing data much better. Specifically, the particular demands in early life demand maintenance of tolerance and balancing of pro-inflammatory stimuli. As a result, the threshold required to initiate immune effector responses is appropriately set higher in early vs. later life. However, once this higher set point is reached, an immune response of substantial magnitude is unleashed that can lead to higher immune pathology. In this context, the clinically observed increased risk for severe infection in early life is best viewed as an imbalance of the phylogenetically selected beneficial survival programs vs. specific environmental demands exerted on the individual during ontogeny. It follows that increased protection from infectious diseases in early life could benefit from an increase of homeostatic stimuli and a decrease rather than increase of immune effector responses.

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15:30-17:00

Breakout session

3 talks Show detail Hide detail

Chairs

Professor Beate Kampmann, Imperial College London, UK and MRC Unit The Gambia

Dr Kirsty Le Doare, Imperial College London, UK

15:30-16:30 Breakout session: What are the areas of maternal immunity that we need to focus on as research priorities and thoughts on how to do this?

15:30-16:30 Breakout session: What are the areas of neonatal immunity that we need to increase our understanding of as research priorities and how can we do this?

16:30-17:00 Discussion and feedback from sessions

14 February

Session 3 09:00-12:30

Immunological opportunities to protect neonates

4 talks Show detail Hide detail

Chairs

Dr Kirsty Le Doare, Imperial College London, UK

09:00-09:30 Age-specific adjuvants for precision vaccines

Dr Ofer Levy, Boston Children's Hospital and Harvard Medical School, USA

Abstract

Vaccines are the most effective biomedical intervention to reduce the heavy burden of early life infection, but often demonstrate suboptimal immunogenicity in early life necessitating multiple boosting doses. Waning immunity to some infant vaccines further limits their effectiveness. Approaches to enhance early life immune responses include identification of adjuvants that increase vaccine immunogenicity. As adjuvants engage innate immune pathways that are often species- and age-specific, the Levy Lab has developed a range of human neonatal and adult in vitro assay platforms to model innate and adaptive immune responses. Human in vitro modelling has identified adjuvants and adjuvant combinations active towards newborn and infant antigen-presenting cells in vitro and that enhance immunogenicity of vaccinal antigens in newborn animals in vivo. Overall, technical advances including human in vitro modelling, genetics and systems biology are ushering in a new era in which precision medicine is brought to vaccinology. In this context, Levy and colleagues recently established the Precision Vaccines Program, a platform for international collaboration to develop vaccines targeted to vulnerable populations such as the very young.

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09:45-10:15 Nutritional factors modulating the neonatal immune response

Dr Sarah Prentice, London School of Hygiene & Tropical Medicine, UK

Abstract

The neonatal immune response may be modulated by the nutrition of a mother during gestation and by post-natal infant nutritional factors. 

In principle there are several pathways by which an expectant mother’s nutrition could modulate her baby’s immune response. This lecture will briefly outline: 1) existing evidence that nutritionally-mediated epigenetic changes occurring peri-conceptionally could preset immune responsiveness; 2) weak evidence that nutritional interventions could alter transplacental antibody transfer; and 3) evidence from prenatal supplementation trials with neonatal mortality as their endpoint. 

Post-natal nutrition could also modulate immune responses over and above the importance of early colostrum provision. This talk will focus on the two nutrients that have received greatest attention: vitamin A and iron. 

Meta-analysed evidence that very early administration of high-dose vitamin A could reduce early neonatal mortality was unclear with high heterogeneity between positive studies in Asia and null/negative studies in Africa. This prompted three major new trials that yielded similar results; some evidence of benefit in Asia, but evidence of harm in Africa. WHO currently does not recommend neonatal vitamin A.

Iron is a major mediator of bacterial growth. Recent studies demonstrated that term neonates display a rapid hepcidin/IL6-mediated hypoferraemia and that post-natal serum is relatively bacteriostatic against common causes of neonatal septicaemia compared to cord serum. Further studies are underway to test whether premature and low-birthweight infants display the same protective response. Oral hepcidin agonists currently under development could potentially be deployed alongside antibiotics and hence augment the therapeutic arsenal in the face of antimicrobial resistance.


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11:00-11:30 The role of breast milk on the infant microbiome and disease

Dr Pia S. Pannaraj, Keck School of Medicine, University of Southern California and Division of Infectious Diseases, Children’s Hospital Los Angeles, USA

Abstract

The establishment of the infant microbiome has lifelong implications on health and immunity. The complex relationship between the microbial communities and infant immune development is only beginning to be realised. Multiple studies have shown the importance of breastfeeding in reducing chronic diseases such as atopy, diabetes, obesity and inflammatory bowel disease. This talk will review what is known about microbial communities in breast milk and microbial seeding of the infant gut through breastfeeding.

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11:45-12:15 Manipulation of the neonatal microbiome – pitfalls and opportunities

Dr Tobias Strunk, King Edward Memorial Hospital for Women, Princess Margaret Hospital for Children and UWA Centre for Neonatal Research and Education, Australia

Abstract

Infections are the second most common cause of the estimated 4 million annual deaths in young children around the world. Compared to the achievements in combatting infections in infants and young children, the reduction in infectious morbidity and mortality in the newborn period has been inadequate. The majority of deaths due to infections occur in resource-poor settings. Novel simple, safe and affordable interventions to reduce the burden of infections in this population are therefore urgently needed and require careful and rigorous scientific assessment.

Our understanding of the neonatal microbiome is evolving rapidly and emerging evidence highlights its relevance for short- and long-term health, including infectious diseases, cardiovascular and metabolic wellbeing as well as immune-mediated conditions such as asthma and allergies. Many well-intended routine perinatal interventions may have unexpected and lasting effects on the neonatal microbiome. This talk will review current knowledge relating to the ontogeny of the neonatal microbiome and its impact on health and disease. Further, it will explore the effects of current routine and potential future interventions on the neonatal microbiome, such as feeding practices, probiotic supplementation and neonatal skin care.

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12:30-13:30

Lunch

Session 4 13:30-17:00

Maternal immunisation

2 talks Show detail Hide detail

Chairs

Professor Beate Kampmann, Imperial College London, UK and MRC Unit The Gambia

13:30-14:00 Current research in maternal immunisation

Dr Flor Munoz-Rivas, Baylor College of Medicine, USA

Abstract

Immunisation of women during pregnancy is an accepted strategy to protect mothers and infants against infectious diseases during a period of high vulnerability. As a public health intervention, maternal immunisation has the potential to reduce the morbidity and mortality associated with pathogens that affect the mother, the newborn, or both. Maternal immunisation with tetanus, pertussis and influenza vaccines results in direct protection of the mother and the newborn infant. Group B streptococcus and Respiratory Syncytial Virus (RSV) are infections that could be prevented through immunisation of pregnant women with safe and effective vaccines that are currently under clinical investigation. This presentation will review the rationale, safety, effectiveness, acceptability and potential impact of the vaccination of women during pregnancy. Challenges associated with the development and implementation of clinical trials of vaccines administered during pregnancy will be discussed.

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14:15-14:45 Current research in neonatal immunisation

Dr Elizabeth Whittaker, Imperial College London, UK

Abstract

The current vaccine schedule has successfully reduced the incidence of serious infectious diseases in young children and the majority of deaths in children less than five years now occur in the neonatal period, with neonatal infections accounting for up to a third of deaths in newborns. A number of challenges exist to neonatal vaccination including safety concerns (both immunological and clinical), demonstration of vaccine efficacy and public acceptance. Recent advances in our understanding of neonatal immunology have led to a renewed interest in neonatal immunisation. Currently hepatitis B, polio and the BCG vaccine are given at birth. Hepatitis B vaccine is effective at reducing mother to child transmission of infection, but long-term protection remains under investigation. The BCG vaccine has up to 80% efficacy at protecting newborns and infants from disseminated TB disease. Recent studies of acellular pertussis and pneumococcal vaccine given at birth have proven they are well tolerated and immunogenic. Ongoing research to understand how neonatal vaccine responses are elicited, and to identify optimal adjuvants and formulations is required to reduce the disease burden in this group.

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15:30-16:15

Breakout session

4 talks Show detail Hide detail

Chairs

Dr Chrissie Jones, St George's, University of London, UK

Dr Elizabeth Whittaker, Imperial College London, UK

Dr Kirsty Le Doare, Imperial College London, UK

15:30-16:15 Breakout session: Future strategies for maternal immunisation

15:30-16:15 Breakout session: Other immunomodulatory strategies

15:30-16:15 Breakout session: Future strategies for neonatal immunisation

16:15-17:00 Summary of discussions and closing remarks

Reducing neonatal infectious morbidity and mortality: joining up our thinking

Theo Murphy scientific meeting organised by Dr Kirsty Le Doare, Dr Elizabeth Whittaker, Professor Beate Kampmann and Dr Chrissie Jones.

Kavli Royal Society Centre, Chicheley Hall Newport Pagnell Buckinghamshire MK16 9JJ